The Medicinal Chemistry and Lead Development Core (MCLDC) is a key component of the Antiviral Drug Discovery and Development Center, contributing to the goals of each of the individual projects. The MCLDC will provide hit-to-lead analysis, synthetic chemistry, structure-activity relationship (SAR) data and analysis, computational support, and lead optimization chemistry to further the CETR's goal of developing new replication inhibitors and other broad-based therapeutics for the treatment of emerging pathogens. In this role, the MCLDC, in conjunction with the Screening Core (SC), will be the central focus of the translational research component of the program. As the SC optimizes the novel assays developed by various Research Projects, and subsequently prosecutes the screening campaign, it will be the function of the MCLDC to assess the quality ofthe hit compounds that emerge, and ultimately to convert novel, tractable hits into potential clinically useful drugs with optimized biological and biophysical properties. As such, the MCLDC will work closely with both the SC and each of the Research Project teams. As new chemical entities are prepared during the lead optimization process, because of the anticipated synthetic throughput the SC will generally test these analogs in a primary assay in order to drive the SAR investigation. As described in detail below, appropriate compounds will also be provided to the various Research Project teams for advanced studies including efficacy, mechanism of action, and other experiments. The resulting data about these compounds, generated by the SC and Research Projects, will then be analyzed by the MCLDC in order to drive the iterative drug discovery program to completion. The MCLDC will incorporate key members of the SC and Research Project teams into the prioritization and decision making procedures. The end result of this process will be the identification of novel drugs appropriate for IND applications.